1. Field
Provided herein are methods of predicting an effect of a c-Met inhibitor or selecting a subject for application of a c-Met inhibitor. The methods comprise measuring Hsp90 protein levels and/or expression levels of an Hsp90 coding gene. Further provided are methods of monitoring an effect of a c-Met inhibitor comprising measuring Hsp90 protein levels and/or expression levels of an Hsp90 coding gene. Also provided are methods of decreasing a resistance to a c-Met inhibitor comprising administering an Hsp90 inhibitor to a subject and methods of treating and/or preventing cancer comprising co-administering an Hsp90 inhibitor and a c-Met inhibitor to a subject.
2. Description of the Related Art
The term “biomarker” generally refers to a measured characteristic which may be used as an indicator of some change caused in an organism by an external factor. Active studies have recently been made to apply biomarkers to the diagnosis of various diseases, such as cancer, stroke, dementia, etc., and to the prediction or monitoring of therapeutic effects of some agents. Among biomarkers relevant to drug development are pharmacodynamic markers (PD markers) for indicating whether drugs are functionally effective in vivo, and predictive markers for indicating the most likely response to particular drugs before administration. The use of such markers is helpful in establishing the clinical strategy of drugs. For example, a predictive marker, designed to indicate sensitivity or resistance to drug action, may be applied to the selection of patients to allow for more effective drug therapy while the action mode of a drug in individual patients can be monitored with a pharmacodynamic marker, which together can lead to the establishment of effective therapeutic strategies. Further, even in the absence of a predictive marker, a pharmacodynamic marker permits the early monitoring of responses to a drug, thus discriminating a drug-effective group from a drug-ineffective group in an early stage. Consequentially, more effective and successful drug therapies can be materialized. In addition, when applied to the monitoring of responses to a drug as a function of concentrations, a pharmacodynamic marker can be an index for calculating suitable doses of the drug.
Cancer is one of the leading causes of death. Although the development of medical techniques has brought about a remarkable progress in cancer therapy, the 5-year survival rate has only improved by 10% over the past two decades. This is because cancer characteristics, such as rapid growth, metastasis, etc., make it difficult to diagnose and treat within a suitable time. The introduction of suitable biomarkers to cancer therapy would identify the characteristics of cancer to increase the opportunity of applying a suitable therapeutic in an optimal time, whereby cancer treatment could reach high success rates. For example, patients with lung cancer may differ from each other in cancer classification, genotype, and protein secretion, and thus must be treated with different, proper therapeutics. For chemotherapy using a specific drug, a corresponding biomarker, if present, would reduce the number of erroneous trials and increase possibility of success. In this regard, it is very important to explore biomarkers for predicting or monitoring the effect of anti-cancer therapeutics. A proper biomarker, if successfully exploited, can make a great contribution to the utility and value of anti-cancer drugs and the success rate of treatment with them.
c-Met is a receptor for hepatocyte growth factor (HGF) that possesses tyrosine kinase activity. Hepatocyte growth factor acts as a multi-functional cytokine which binds to the extracellular domain of the c-Met receptor to regulate cell division, cell motility, and morphogenesis in various normal and tumor cells. c-Met is a proto-oncogene that takes part in a variety of mechanisms responsible for the development of cancer independent of HGF binding, such as oncogenesis, cancer metastasis, the migration and invasion of cancer cells, and angiogenesis. Thus, c-Met has attracted intensive attention as a target for anti-cancer therapy. For example, targeted therapies, such as antibodies against c-Met, have been developed.
c-Met-targeting drugs might be more effective at treating cancer if there is a biomarker that is useful in predicting and monitoring the therapeutic effect of the drug, or in selecting patients suitable for the drug therapy and thereafter monitoring patient responses to the drug.
There is a need for biomarkers useful for predicting the effect of the c-Met targeting drugs to select a subject who is suitable for application of the c-Met targeting drugs, and/or for monitoring the responsiveness of a patient who has been treated with the c-Met targeting drugs to establish more effective treatment strategies using the c-Met targeting drugs.